j o u r n a l o f f o o d a n d d r u g a n a l y s i s 2 3 ( 2 0 1 5 ) 6 1 9 e6 2 9

Available online at www.sciencedirect.com

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Review Article

Impact of chitosan composites and chitosan

nanoparticle composites on various drug delivery
systems: A review
M.Abd Elgadir a, Md.Salim Uddin b, Sahena Ferdosh c, Aishah Adam a,
Ahmed Jalal Khan Chowdhury c, Md.Zaidul Islam Sarker b,*
a

Department of Pharmacology and Chemistry, Faculty of Pharmacy, Universiti Teknologi MARA, 42300 Bandar
Puncak Alam, Selangor, Malaysia
b
Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia,
Kuantan Campus, 25200 Kuantan, Pahang, Malaysia
c
Faculty of Science, International Islamic University Malaysia, Kuantan Campus, 25200 Kuantan, Pahang, Malaysia

article info

abstract

Article history:

Chitosan is a promising biopolymer for drug delivery systems. Because of its beneficial

Received 2 May 2014

properties, chitosan is widely used in biomedical and pharmaceutical fields. In this review,

Received in revised form

we summarize the physicochemical and drug delivery properties of chitosan, selected

28 September 2014

studies on utilization of chitosan and chitosan-based nanoparticle composites in various

Accepted 22 October 2014

drug delivery systems, and selected studies on the application of chitosan films in both

Available online 4 December 2014

drug delivery and wound healing. Chitosan is considered the most important polysaccharide for various drug delivery purposes because of its cationic character and primary

Keywords:

amino groups, which are responsible for its many properties such as mucoadhesion,

chitosan

controlled drug release, transfection, in situ gelation, and efflux pump inhibitory properties

drug delivery system

and permeation enhancement. This review can enhance our understanding of drug de-

nanoparticle composite

livery systems particularly in cases where chitosan drug-loaded nanoparticles are applied.

wound healing

Copyright 2014, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan
LLC. All rights reserved.

1.

Introduction

Chitosan is a natural polysaccharide and is considered the

largest biomaterial after cellulose in terms of utilization and
distribution [1]. It is produced from chitindthe structural
element found in the exoskeleton of crustaceans such as
shrimps, lobsters, and crabs. The shells of these crustaceans

are first removed and then ground into powder, which is

further processed to produce chitosan. Chitosan also occurs
naturally in some microorganisms such as fungi and yeast [2].
Although chitosan is structurally similar to cellulose, it contains, in addition to hydroxyl groups, acetylamine or free
amino groups, which display very different properties from
those of cellulose [3]. Chitosan has attracted attention because

* Corresponding author. Department of Pharmaceutical Technology, Faculty of Pharmacy, International Islamic University Malaysia,
Kuantan Campus, 25200 Kuantan, Pahang, Malaysia.
E-mail address: zaidul@iium.edu.my (Md.ZaidulI. Sarker).
http://dx.doi.org/10.1016/j.jfda.2014.10.008
1021-9498/Copyright 2014, Food and Drug Administration, Taiwan. Published by Elsevier Taiwan LLC. All rights reserved.

620

j o u r n a l o f f o o d a n d d r u g a n a l y s i s 2 3 ( 2 0 1 5 ) 6 1 9 e6 2 9

of its biological properties and effective uses in the medical

field, food industries, and agricultural sector [4]. It shows a
variety of biological activities such as phytoalexin elicitor activity, activation of immune response, cholesterol lowering
activity, and antihypertension activity [5,6]. Similarly, mesoporous silica nanoparticles (NPs) have the ability to efficiently
entrap cargo molecules because of their unique characteristic
of having a huge pore size. They have already been recognized
as a promising drug carrier and have recently become a new
area of interest in the field of biomedical applications [7]. For
instance, Zhu et al [7] focused on the stimuli-responsive
controlled-release systems that responded to tumor cell
environmental changes, such as pH, glucose, adenosine-50triphosphate, glutathione, and H2O2.
Chitosan's therapeutic properties have also been reported
by other researchers, such as inhibition of growth of microorganisms and pain alleviation [8,9] and promotion of hemostasis and epidermal cell growth [10]. However, some
researchers are interested in the potential applications of
chitosan for medical and pharmaceutical purposes. The
increased interest in chitosan, particularly its use in the
pharmaceutical field, is attributed to its favorable properties
such as biocompatibility, ability to bind some organic compounds, susceptibility to enzymatic hydrolysis, and intrinsic
physiological activity combined with nontoxicity and heavy
metal ions [11e13]. These properties are particularly
amenable to a wide variety of biomedical applications in drug
delivery and targeting, wound healing, and tissue engineering,
as well as in the area of nanobiotechnology. Chitosan has
attracted attention as a material for drug delivery biomedical
applications in the past few years because of its biological and
physicochemical properties, leading to the recognition of
chitosan as a drug delivery element and a promising material
specifically for the delivery of macromolecules [14e16]. In this
regard, chitosan-based delivery systems range from microparticles to NP composites and films. However, there are
several drawbacks in the use of chitosan for drug delivery
systems. The main drawback is its poor solubility at physiological pH owing to the partial protonation of the amino
groups, thereby causing presystemic metabolism of drugs in
intestinal and gastric fluids in the presence of proteolytic
enzymes. To overcome these inherent drawbacks, various
derivatives of chitosan such as carboxylated, different conjugates, thiolated, and acylated chitosan have been used in
drug delivery systems [17,18]. Researchers reported on the
goals of using chitosan as an excipient for drug delivery systems [19e23]. Therefore, the main objective of this review is to
highlight and investigate the application of chitosan and
chitosan-based NP composites in drug delivery systems and to
provide some insight for its future potential.

2.
Preparation and physicochemical
properties of chitosan
Fig. 1 shows the structures of chitin, cellulose, and chitosan.
Chitosan is recognized as a linear binary heteropolysaccharide
composed of b-1,4-linked glucosamine with various degrees of
N-acetylation of glucosamine residues [24,25]. It is prepared
from chitin by alkaline N-deacetylation [24,26] using

Fig. 1 e Structures of (A) chitin, (B) cellulose, and (C)

chitosan.

concentrated sodium hydroxide (NaOH) solutions at high

temperatures for a long period. Another method for the production of chitosan is N-deacetylation using enzymes under
relatively mild conditions [27]. The commercially available
chitosan is mostly derived from chitin of crustaceans by
alkaline N-deacetylation because it is easily obtainable [28].
The production of chitosan involves a two-step process. The
first step is extraction of chitin [a linear chain consisting of Nacetyl-D-glucosamine (2-acetamido-2-deoxy-b-D-gluconopyranose) joined together by b (1/4) linkage] and removal of
calcium carbonate (CaCO3) from crustaceans' shells using
dilute hydrochloric acid and deproteination with dilute
aqueous NaOH. In the second step, 40e50% aqueous NaOH at
110e115
C is used for deacetylation of chitin for several hours
without oxygen. When the degree of deacetylation exceeds
50%, then chitosan is produced [29]. Chitin with a degree of
deacetylation of  75% is also recognized as chitosan [28].
The degree of deacetylation and molecular weight are the
two fundamental parameters that can affect the properties
and functionality of chitosan [26,30]. These properties include
solubility, viscosity, reactivity of proteinaceous material
coagulation, and heavy metal ion chelation [31e33], and
physical properties of films formulated using chitosan such as
tensile strength, elasticity, elongation, and moisture absorption [34]. Chitosan is soluble in aqueous acidic solutions, but
insoluble in both water and alkaline solutions [25]. The majority of polysaccharides are usually found neutral or negatively charged in an acidic environment. When dissolved, the
amino groups (eNH2) of the glucosamine are protonated to
eNH
3 [35], and the cationic polyelectrolyte readily forms
electrostatic interactions with other anionic groups [36].
Therefore, the cationic chitosan molecule interacts with
negatively charged surfaces that modify its physicochemical
characteristics [2,37]. These modifications of chitosan molecules are the source of its unique functional properties.

j o u r n a l o f f o o d a n d d r u g a n a l y s i s 2 3 ( 2 0 1 5 ) 6 1 9 e6 2 9

3.

Drug delivery properties of chitosan

3.1.

Anionic drug delivery properties

When a technique of drug discharge cannot be achieved by

using a simple drug dissolution process such as diffusion,
membrane layer handle along with erosion as well as osmotic
systems, retardation mediated by ionic relationships is often
used. The latter technique can be carried out with regard to
cationic drugs by using anionic polymeric excipients such as
polyacrylates, alginate, or carboxymethylcellulose salt. However, in anionic drug delivery systems, chitosan is the sole
selection. Chitosan was used as a medication provider matrix
to investigate medication release devices for the anionic
medication naproxen [38]. It was found that the interactions
between chitosan and the therapeutic agent was more
evident, and stable complexes can also be formed from which
this medicine can be produced, actually spanning a more
extended period counted on an ionic cross-linking. For
example, the delivery systems of enoxaparin/chitosan nanoparticulate provided more stable complexes and resulted in
significantly improved drug uptake [39]. Some anionic polymeric excipients such as carrageenan, pectin, alginate, and
polyacrylates can be homogenized with chitosan, leading to
high-density, relatively stable complexes. However, a similar
result can be achieved by homogenizing chitosan with an
alternative to multivalent anionic and inorganic polymer anions such as sulfate or tripolyphosphate (TPP) [40].

3.2.

Mucoadhesive properties

The mucoadhesive properties of chitosan are probably

attributable to its cationic character. Furthermore, hydrophobic interactions may help with the mucoadhesive components. The mucoadhesive properties of chitosan are weak
as compared with various anionic polymeric excipients such
as hyaluronic acid, polycarbophil, and carbomer [41]. In order
to attain substantial mucoadhesive attributes, a polymer
should have high cohesive properties because adhesive bond
normally fails within the mucoadhesive polymer as opposed
to involving the polymer along with the mucus gel layer.
Regarding chitosans, these cohesive properties tend to be
comparatively weak. It may be improved by the formation of
complexes with multivalent anionic drug treatments, multivalent anionic polymeric excipients, and also multivalent
inorganic anions. This strategy is effective to a very limited
extent, as the cationic substructures of chitosan being
accountable for mucoadhesion via ionic interactions while
using the mucus are blocked in such cases. Lueben et al [42]
demonstrated a significantly improved oral bioavailability
involving buserelin when being administered in rats with
mucoadhesive polymers, for instance, chitosan and carbomer.
However, this particular effect could not be attained anymore
when chitosan was mixed with polyanionic carbomer in the
same formulation. More cationic character of the polymer is
provided by the trimethylation of the primary amino group of
chitosan. It was found that when trimethylated chitosan is
added to PEGylated, its mucoadhesive properties were
improved up to 3.4-fold [43]. The mucoadhesive properties of

621

chitosan can be substantially improved as a result of the

immobilization of thiol groups on it. It was reported that chitosan is able to form disulfide bonds with mucus glycoproteins
when found with the mucus gel layer, and this phenomenon
makes it the most mucoadhesive polymer [44].

3.3.

Gelling properties

As hydrogels form, one advantage of in situ gelling properties

can be achieved when the pH-dependent hydrostability of
chitosan is properly addressed. Gupta and Vyas [45] improved
an in situ gelling delivery system by using a mixture of polyacrylic acid and chitosan. They observed that the resulting
formulation was in a liquid state at pH 6.0 even though the
same formulation underwent a rapid transition to viscous gel
phase at pH 7.4. Further improvements through thiolation
may also enhance the in situ gelling characteristics of chitosan.
As a result of the access of oxygen on mucosal surfaces, for
instance, nasal mucosa or ocular surfaces, immediately after
the mixture is applied in liquid form using oxygen-free single
unit forms, a cross-linking process via disulfide bond formation takes place, causing a significant increase in viscosity.
Based on the cross-linking properties, the viscosity
increased 16,500-fold in a period of 20 minutes using aqueous
1% (m/v) of chitosanethioglycolic acid conjugate [46].

3.4.

Gene expression properties

Chitosan was also modified to improve its properties for gene

expression purposes. For instance, the self-branching of chitosans was used as a strategy to improve its gene transfer
properties, and this can be carried out without compromising
the safety profile [47]. In this respect, self-branched trisaccharide-substituted chitosans, in addition to a self-branched
molecular mass of 11e71 kDa, were synthesized, characterized, and also compared in contrast to their own linear
counterparts with respect to transfection efficiency.
The results revealed that self-branched chitosans could
yield gene expression levels two as well as five times greater
than that of Lipofectamine and Exgen, respectively. In another
investigation, thiolated chitosan forming intrachain bonds of
disulfide was used as a good strategy to stabilize the chitosan/
plasmid NP complex, resulting in higher stability properties
toward nucleases [48]. In addition, owing to the reducing conditions of the cytoplasma, the plasmid was mainly released in
the target cells because the disulfide bonds were largely cleaved
there, resulting in the release of the plasmid at the target site.
The transfection rate of the thiolated chitosan/plasmid NP
complex was found to be five times higher compared with that
of the unmodified chitosan/pDNA NP complex. Owing to the
trimethylation of the remaining primary amino groups, this
strategy was further improved by raising the cationic character
of thiolated chitosan [49]. Furthermore, chitosan/cyclodextrin
and PEGylated chitosan NPs were identified as promising tools
for DNA-based drug delivery [50,51].
In contrast to small molecules, where a controlled release
of anionic drugs can be achieved, stable complexes with chitosan can be formed using comparatively large polyanionic
molecules such as small interfering RNA and DNA-based
drugs. If the ratio of the cationic polymer is sufficiently high

Prevents disappearance of Zidovudine

in human plasma and prolong its shelf life

Vaginal delivery of chlorhexidine digluconate

Management of extraocular diseases

Delivery of drug for skin

Chitosan oligomerezidovudine
composite

Chitosanesodium alginate tablet

Chitosanecyclosporin A

Chitosanepolyelectrolyte films

Purpose of utilization

Delivery of resveratrol to the colon

Many studies have been conducted recently using chitosan as

a drug delivery biomaterial to treat diseases such as cancer
[61], optical diseases [62], and colon diseases [63]. Table 1
shows a selection of studies on the use of chitosan composites for drug delivery applications. A systematic series of Ntrimethyl chitosan chloride polymer synthesized from

Chitosanezincepectin composite

4.
Selected studies on utilization of chitosan
composites for drug delivery systems

Table 1 e Selected studies on utilization of chitosan composites for drug delivery applications.

Based on the positive charges of chitosan, it was found that

these charges are responsible for the mechanism of permeation enhancement, which can interact with the cell membrane of chitosan, resulting in a structural reorganization of
tight junction-associated proteins [55]. A primary amino
group that led to a more pronounced cationic character using
the trimethylation strategy did not lead to further improvements of permeation enhancing properties. It was demonstrated that the permeation enhancing properties and toxicity
to a large extent were attributable to the structural properties
of chitosan including the degree of deacetylation and molecular mass [56]. Chitosans with high molecular mass and high
degree of deacetylation exhibited a comparatively higher increase in epithelial permeability, which could be due to molecular mass and other permeation enhancing polymers such
as polyacrylates [57]. Various in vivo studies can be used to
confirm this permeation enhancing effect. A 2-fold improvement of the oral bioavailability of ganciclovir was demonstrated owing to the coadministration of chitosan [58].
Chitosan can be combined with other permeation enhancers
because it acts in a completely different manner from these
enhancers, leading to an additive or even a synergistic effect.
Using this strategy, the oral bioavailability of ganciclovir could
even be improved by 4-fold, using a combination of sodium
dodecyl sulfate and chitosan compared with just a 2-fold
improvement with sodium dodecyl sulfate alone. Recently, it
was reported that chitosan NPs exhibit only in the first
segment of the duodenum a permeation enhancing effect for
small peptides. The permeation enhancing effect was
enlarged over the entire duodenum owing to the addition of
cyclodextrin [59]. However, >30-fold further improvement in
the permeation enhancing properties of chitosan on certain
mucosal membranes can be achieved because of thiolation
[60].

Findings

Permeation enhancing properties

Name of chitosan composites

3.5.

Integration of optical pH-sensing

in the complex, NPs exhibiting a positive zeta potential can be

formed. Because of the small size of these particles and the
net positive charge, endocytosis was achieved particularly
when the sizes of the particles were smaller than 100 nm [52].
From a toxicology viewpoint, chitosan is comparatively
recognized as a less toxic polymer than other cationic polymers such as polyarginine, polylysine, and polyethyleneimine
[53]. This property makes chitosan a promising excipient for
nonviral gene delivery systems. It was reported that the
bioavailability of DNA-based drugs delivered into the body can
be improved if chitosaneDNA-based drug complexes are
protected to some extent toward degradation by DNAses [54].

Chitosan-based responsive hybrid nanogels exhibit a nonreversible pH-sensitive property and a

significant cytotoxicity after 24 h treatment. It is critical to construct highly stable biopolymer-hybrid
nanogel quantum dots [43].
Formulation prepared at pH 1.5, 1% chitosan, 120 min cross-linking time, and pectin/drug ratio of 3:1
demonstrated the best colon-specific drug release [79].
The study indicated longer mean retention time for chitosan oligomerezidovudine composite with
values of about 1.5 h vs. 0.59 h for zidovudine alone. Chitosan oligomerezidovudine composite was
found to have accumulated in the kidney other than heart, liver, spleen, lung, and brain, and the drug
had a shelf life of 12 h [66].
Tablet containing 6% chitosan, 24% sodium alginate gave the best result of drug release [70].
Enhancement of therapeutic index of clinically challenging drugs with potential application at
extraocular level and achievement of fast drug release and therapeutic concentrations in external ocular
tissues during a period of 24 h [122].
The films gave significantly different drug release and drug permeation through the skin [123].

j o u r n a l o f f o o d a n d d r u g a n a l y s i s 2 3 ( 2 0 1 5 ) 6 1 9 e6 2 9

Chitosan-based responsive hybrid

nanogels

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different chitosans based on molecular weight (low, medium,

and high molecular weight) have been coformulated into a
hydrogel with polyethylene glycol (PEG) and glycerophosphate
and investigated for nasal drug delivery [64]. The authors
found that hydrogels derived from N-trimethyl chitosan with
high or medium average molecular weight exhibit relatively
short solegel transition times at physiologically relevant
temperatures. The same hydrogels display good waterholding capacity and strong mucoadhesive potential. They
revealed that an aqueous hydrogel formulation, which was
derived from N-trimethyl chitosan of medium average molecular weight, appears particularly promising because it
exhibited the most favorable rheological and mucoadhesive
behaviors and a solegel transition that occurs at 32.5
C within
7 minutes.
Chitosan was also investigated as an injectable vehicle for
drug delivery in the presence of sodium bicarbonate (NaHCO3)
[65]. The hydrogels of chitosan/NaHCO3 system showed
porous morphologies with some diversification depending on
the NaHCO3 concentration, which affected their erosion and
drug release rate behaviors. An in vivo gelation test was performed via a dorsal subcutaneous injection of chitosan/
NaHCO3 solution in adult SpragueeDawley rats. Exactly 2%
(w/v) of chitosan solution without NaHCO3 was also administered as a control. Sterile solutions were prepared via UV
sterilization of solid chitosan powder, 0.22 mm filtration of 1%
acetate acid solution and NaHCO3 solutions, and sterilized
chitosan solution and chitosan/NaHCO3 mixtures. An
aqueous urethane solution was injected intraperitoneally to
anesthetize the rats. Each injection was 0.4 mL in volume and
performed subcutaneously through a syringe equipped with a
G2 gauge needle. The formation of in situ gels suggested that
such systems have promising applications in injectable drug
delivery. The drug delivery system prepared from chitosan
oligomerezidovudine composites for the in vitro release of
zidovudine was investigated [66]. A conjugate study was
confirmed in mice plasma and renal homogenate. The pharmacokinetics study indicated a longer mean retention time
for the chitosan oligomerezidovudine conjugate with values
of about 1.5 hours compared with 0.59 hour for zidovudine
alone. The chitosan oligomerezidovudine conjugates were
found to accumulate (aside from the heart and the liver) in the
lung, spleen, brain, and kidney after their in vivo administration. The study concluded that chitosan oligomerezidovudine
conjugates have the potential to be developed into a renaltargeting drug delivery system.

5.
Selected studies on chitosan-based NPs
for drug delivery systems
Nowadays, it is considered that nanomedicine will lead
breakthroughs for the detection, diagnosis, and treatment of
cancer [67]. Chitosan NPs are a drug carrier with the advantage
of slow or controlled drug release, which improves drug solubility and stability, enhances efficacy, and reduces toxicity.
In vitro and in vivo studies have also shown that chitosan has
antitumor effects, leading to good prospects for their application as a supplementary antitumor drug and drug carrier
[68]. Chitosan-based nanostructures predominantly work on

623

the involved chemical cross-linking within the polymer chain.

Earlier chitosan/silica nanocomposites were formed using the
reaction of hydroxyl groups on chitosan monomers with tetramethoxysilane. The first data presented involved chitosan
nanospheres for drug delivery applications [69]. The authors
used the water-in-oil (w/o) emulsion method, which was followed by glutaraldehyde cross-linking of the chitosan amino
groups. They produced nanospheres loaded by 5-fluorouracil,
an anticancer drug. These studies further revealed the feasibility of reproducible synthesizing stable nanosized chitosan
particles, which can entrap and deliver drugs [70]. One of
chitosan's properties is its ability to form gel upon contact
with special polyanions, a process referred to as ionotropic
gelation, which occurs as a result of the formation of intra
and inter cross-linkages within/between polymer chains
mediated by the polyanions.
Based on ionotropic gelation of TPP with chitosan, chitosan
NPs have been developed for drug encapsulation [71,72]. This
simple technique involves mixing of the acidic phase (pH 4e6)
containing chitosan with an alkaline phase (pH 7e9) containing TPP. NPs were immediately formed based on the
mixing of these two phases through intra- and intermolecular
linkages created between chitosan amino groups and TPP
phosphates. Insulin-loaded chitosan NPs have also been successfully prepared using a TPP solution mixed with insulin
and then adding the mixture to chitosan solution under constant stirring [73]. In brief, various concentrations of chitosan
and TPP were dissolved in acetic acid (pH 4) and purified
water, respectively. Different volumes of the TPP solution was
mixed with 4 mL of the chitosan solution through a syringe
needle under magnetic stirring at room temperature, and
chitosan NPs were present in the suspension. Insulin-loaded
chitosan NPs were formed spontaneously upon the incorporation of the TPP aqueous solution containing insulin to the
chitosan acetic acid solution. The size of chitosan NPs were
300e400 nm with a surface positive charge ranging from 54
to 25 mV. In this study, the ability of chitosan NPs to enhance
both relative bioavailability and intestinal absorption of insulin was investigated by monitoring the glucose level of
plasma in alloxan-induced diabetic Wistar male rats. Various
doses of insulin-loaded chitosan NPs were orally administrated. The stable positively charged chitosan NPs showed
particle sizes within the range of 250e400 nm, and an insulin
association ratio of up to 80% was used. The in vitro release
investigations indicated an initial burst phase that was pHsensitive. The intestinal absorption of insulin was enhanced
by chitosan NPs to a greater extent than the aqueous solution
of chitosan in vivo. It was noticed that hypoglycemia was
prolonged over 15 hours after the administration of 21.1 IU/kg
insulin loaded in the chitosan NPs. However, the average
bioavailability relative to the subcutaneous injection of free
insulin solution showed up to 14.9%. In another study,
different formulations of chitosan NPs produced by the ionic
gelation of TPP and chitosan were investigated [74]. Drug delivery systems prepared using low molecular weight (LMW)
chitosan NPs and monodisperse using the ionic gelation
technique were also investigated [75]. The results showed that
LMW chitosan NPs has good compatibility with erythrocytes,
and they can be easily attached to the erythrocyte membrane
surface. This indicates that the erythrocyte load of LMW

NP nanoparticle; TPP tripolyphosphate.

These NPs shows potentiality for drug delivery on the epithelial cells of ocular mucosa [124].

These NPs target tumor cells with good efficiency [79].

Chitosan NPs conjugated with doxorubicinedextran

complex
Chitosan NPs labeled with fluorescein
isothiocyanateebovine serum albumin

Delivery of encapsulated of
plasmid DNA
Delivery of encapsulated
dextranedoxorubicin conjugate
Delivery of fluorescein
ChitosaneDNA NPs

These stable nanosized chitosan particles can entrap and deliver drugs in tumor cells [79].

Chitosan NPs enhanced both the relative bioavailability and intestinal absorption of insulin, resulting in
lower blood glucose level in rats [73].
ChitosaneDNA NPs protect the encapsulated plasmid DNA from nuclease degradation [77].
ChitosaneTPP NPs loaded with insulin

Purpose of utilization

Delivery of 5-fluorouracil for cancer

treatment.
Delivery of insulin for diabetics

Chitosan was also used in the preparation of films for drug

delivery systems [85e87]. Films prepared using chitosan have
been utilized for oral delivery of many drugs such as chlorhexidine digluconate [88], 5-fluorouracil [89], mitoxantrone
[90], cytarabine [91], and paclitaxel [92]. The characteristics of
chitosan including the drug delivery behavior of nanocomposite films prepared from mixtures of chitosan and
organic rectorite (OREC), which is a type of layered silicate,
were investigated [93]. The films of chitosan and chitosaneOREC nanocomposite were prepared with different chitosan/OREC mass ratios (2:1, 6:1, 12:1, 20:1, 50:1) and dissolved
in a 2% (w/v) aqueous acetic acid to obtain 2% (w/v) chitosan
and chitosan/OREC nanocomposite films. The films exhibited

Chitosan nanospheres loaded by 5-fluorouracil

6.
Selected studies on chitosan films for drug
delivery systems

Table 2 e Selected studies on utilization of chitosan NP composites for drug delivery systems.

chitosan can be used as a potential vascular drug delivery

system.
The complex coacervation technique was previously used
to prepare chitosaneDNA NPs [76,77]. The phosphate and
amino groups were used in a ratio between 8 and 3, respectively, in the presence of chitosan. This particle size was
optimized to 100e250 nm range using a narrow distribution. It
is possible that chitosaneDNA NPs could partially protect the
encapsulated plasmid DNA via the degradation of nuclease.
Coalescence and emulsionedroplet coalescence methods
were reported by Tokumitsu et al [78]. They used the principles of both emulsion cross-linking and precipitation. With
this method, instead of cross-linking in the stable droplets,
precipitation is elicited by allowing the coalescence of small
chitosan droplets with NaOH droplets. A stable emulsion
containing an aqueous solution of chitosan combined with
the drug to be loaded is stated in liquid paraffin. At that time,
another stable emulsion containing aqueous chitosan mixed
with NaOH is produced in a similar manner. When both
emulsions are combined under high-speed stirring, droplets
of each and every emulsion would randomly collide [79].
The preparation of ultrafine polymeric NPs with a narrow
size distribution may be achieved using a reverse micellar
medium. Such particles can be prepared using the aqueous
core of the reverse micellar droplets as a nanoreactor. The size
of these very narrow and monodispersed reverse micellar tiny
droplets normally lies between 1 nm and 10 nm [80], which
turns them into potential and promising NPs in drug delivery
investigations. A method to encapsulate doxorubicinedextran
conjugates in chitosan NPs was used by Mitra et al [81]. In this
method, an organic solvent was applied to dissolve the surfactant for preparing reverse micelles. Several studies have
been done on the self-assembly of chemically modified chitosan into NPs with an eye toward delivering macromolecules
[82e84]. Fractional conjugation connected with PEG at a basic
pH was proven to yield self-aggregation via an amide linkage
to soluble chitosan [84]. After incubation in phosphate buffer
saline, these kinds of aggregates could trap insulin because
electrostatic interactions were developed between the unconjugated chitosan monomers and the anionic residues of
protein. Table 2 shows a selection of studies on the utilization
of chitosan NP composites for drug delivery systems.

Findings

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Name of chitosan NP composites

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the strongest antibacterial behaviors. It was observed that all

films showed equivalent drug release in the initial stages, but
after several hours the release became slower compared to
films prepared using pure chitosan. Chitosan and gelatin solutions were mixed together to obtain two final polymeric
concentrations, F1 (1% w/v) and F2 (2% w/v), and the films
prepared from the mixture were investigated for drug delivery
[94]. The results showed that only the film based on gelatin
alone provided complete drug release owing to its dissolution.
In 30 minutes, films with an excess of chitosan showed a
higher release of drugdup to 83% as compared with 48% of the
drug for films containing greater amounts of gelatin.
Films of chitosan were prepared for dexamethasone delivery [95]. Dexamethasone was loaded in chitosan films at a
percentage of 1.5 (wt.%). Later, the films were dried in a glass
Petri dish at room temperature for 1e3 days until monolayer
films were obtained. An analog procedure was performed to
achieve a bilayer film formation with dexamethasone. Release
tests suggest that the dexamethasoneechitosan films are
potential sustained-release carriers for dexamethasone. It
was also found that the release time of the films was longer
than that of conventional ocular topical delivery dosage
forms. Moreover, a second layer of chitosan film significantly
modified the drug release profile. Therefore, the monolayer
dexamethasoneechitosan film might be considered a promising ocular delivery carrier for dexamethasone in hours and
bilayer dexamethasoneechitosan film in weeks.
Films prepared from chitosan and PEG with ciprofloxacin
hydrochloride as the model drug incorporated at different
concentrations were studied [96]. PEG was used in concentrations of 2.0 wt.%, 3.5 wt.%, 5.5 wt.%, and 8.0 wt.% of total
films. Ciprofloxacin hydrochloride (0.1 g and 0.3 g) was loaded
in the films. From the controlled release tests, it was found
that the release of ciprofloxacin hydrochloride increased with
PEG and decreased with the increase in the amount of drug
loaded in the film. However, the cumulative release amount of
the drug increased significantly. The chitosanePEG films were
also found to be sensitive to pH and ionic strength. In simulated intestinal fluid, a reduction of the ciprofloxacin hydrochloride concentration from 100% to 71% with an increase in
thickness of the film from 35 mm to 85 mm was observed.

7.
Selected studies on wound healing based
on chitosan
Chitosan is used as a wound healing accelerator in many
studies [97e108]. It enhances the functions of inflammatory
cells such as macrophages and polymorphonuclear leukocytes, as well as the production of osteopontin and leukotriene B4, transforming growth factor b1, and platelet-derived
growth factor and fibroblasts [97]. Chitosan also possesses
other biological activities and affects the macrophage function that favors faster wound healing [109]. Moreover, it has
histoarchitectural tissue organization and displays an aptitude to stimulate cell proliferation [110]. The biological properties, especially bacteriostatic and fungistatic properties,
are useful for wound treatment [111]. Films with flexible,
thin, transparent properties prepared from a composite of
chitosanealginate
polyelectrolyte
complex
caused

625

acceleration in healing of incision wounds in the rat model

compared with conventional gauze dressing. It was observed
that the closure rate and appearance of polyelectrolyte
complex-treated wounds were comparable with Opsite1treated wounds [112]. An application of cross-linkable chitosan hydrogel on full-thickness skin incisions made on the
backs of mice significantly induced wound contraction and
resulted in a substantial acceleration of wound closure and
healing compared with the untreated controls [98]. In another
research, an early return to normal skin color in chitosantreated areas was observed [113]. Treatment with chitosan
demonstrated a substantial decrease in treatment time with
minimum scar formation in various animals. The biochemistry and histology of chitosan in wound healing have also
been investigated [114]. It was found that silver sulfadiazine
incorporated with bilayer chitosan wound dressing exhibited
tremendous oxygen permeability, water uptake capability,
and controlled water vapor transmission rate. The dressing
showed excellent antibacterial activity when in vitro culture
was performed for 1 week [115]. Chitosan has been studied
widely as a wound dressing material. Acetate bandage for
wound healing dressing as a topical antimicrobial dressing in
mice was investigated by Burkatovskaya et al [116]. It was
found that the bandage provided important benefits by
reducing the number of inflammatory cells in the wound at
Day 2 and Day 4 and by healing the wound especially during
the early period where its antimicrobial effect is most
important.

8.
Safety assessment of biomedical
application of chitosan and its NP composite
Although nanotechnology is a promising technology offering
great benefits in the biomedical field, current knowledge on
the safety of various NPs in biomedical application is not
sufficient. Generally, chitosan has been considered comparatively safe because of its biodegradable and biocompatible
properties. LMW chitosan is excreted through the kidney,
whereas the excessive molecular weight can be degraded into
fragments suitable for renal clearance [117]. However, the use
of chitosan in unmodified forms is restricted because they are
water-insoluble and highly viscous and have the tendency to
coagulate with proteins at high pH values [118]. Chitosan NPs
exhibit toxic properties, which make chitosan NPs applicable
for cancer treatment. Some studies have reported the cytotoxicity effects of chitosan NPs in vitro [119,120]. A few
research studies have been performed on genotoxicity effects
and skin irritation. An in vivo study also reported that chitosan
NPs affected the mice's survival rate [121]. However, despite
several drawbacks, chitosan is considered a promising agent
for drug delivery systems.

9.

Conclusion

This review summarizes the biomedical application of chitosan and chitosan-based NP composites with emphasis on
drug delivery systems. Chitosan is an important and amazing
material that has so many applications in various fields of

626

j o u r n a l o f f o o d a n d d r u g a n a l y s i s 2 3 ( 2 0 1 5 ) 6 1 9 e6 2 9

drug delivery systems. It is biodegradable and biocompatible,

and can be found in abundance in nature from renewable
sources. Recently, nanochitosan composites have acquired a
remarkable advantage over their conventional counterparts
owing to the presence of a huge surface area, which gives
them additional properties, particularly in terms of biomedical applications. Further study on the drug delivery properties
of chitosan and its NP composites may lead to the realization
of more effective drug delivery systems.

Conflicts of interest
All authors declare no conflicts of interest.

Acknowledgments
This paper is a part of research funded by the Department of
Pharmacology and Chemistry, Faculty of Pharmacy, Universiti
Technologi MARA, Selangor, Malaysia.

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